To fully understand the pathogenic process of human viral diseases animal[unreadable] models are needed. We have developed the SCID-hu mouse as an in vivo[unreadable] system which demonstrates HIV-l-induced pathology closely resembling that[unreadable] seen in human disease. The SCID-hu system employs immunodeficient mice as[unreadable] hosts for human fetal hematopoietic tissue (thymus/liver) grafts, which[unreadable] can be maintained for up to a year. We recently found that these human[unreadable] Thy/Liv grafts in HIV-l-infected SCID-hu mice undergo marked depletion of[unreadable] CD4-positive cells in a manner characteristic of that seen in human HIV-l[unreadable] infection. Thus, we have a model uniquely suited to the study of HIV-I[unreadable] pathogenesis in vivo which avoids the artifacts common to in vitro[unreadable] systems. We will use this model to investigate the molecular mechanisms[unreadable] used by HIV-l to deplete human thymocytes in vivo and will also introduce[unreadable] viruses mutated in the auxiliary genes, nef, vif, vpu, and vpr, to[unreadable] determine the role these genes play in the pathogenic process. Our[unreadable] preliminary data indicate that nef mutants of HIV-l display attenuated[unreadable] growth and cytopathic properties when compared to wild-type virus in this[unreadable] system. Thus, the SCID-hu mouse appears to function as an in vivo system[unreadable] to assess attenuation of HIV-l strains. Site-directed mutations in[unreadable] previously identified "active" regions and/or deletion mutants of the nef[unreadable] gene will be introduced into infectious virus and used in the SCID-hu[unreadable] system to determine the critical regions of nef in vivo. These experiments[unreadable] should increase our knowledge of how HIV-l depletes cells in a lymphoid[unreadable] organ, and provide valuable information regarding the role of viral[unreadable] auxiliary genes on virus replication in vivo. These studies will also help[unreadable] to develop the SCID-hu system as a means of screening "attenuated" viruses[unreadable] which may augment the development of a live attenuated vaccine against[unreadable] AIDS.[unreadable]